Extracellular DNA release, quorum sensing, and PrrF1/F2 small RNAs are key players in Pseudomonas aeruginosa tobramycin-enhanced biofilm formation.

NPJ Biofilms Microbiomes. 2019 May 23;5(1):15

Authors: Tahrioui A, Duchesne R, Bouffartigues E, Rodrigues S, Maillot O, Tortuel D, Hardouin J, Taupin L, Groleau MC, Dufour A, Déziel E, Brenner-Weiss G, Feuilloley M, Orange N, Lesouhaitier O, Cornelis P, Chevalier S

Abstract
Biofilms are structured microbial communities that are the leading cause of numerous chronic infections which are difficult to eradicate. Within the lungs of individuals with cystic fibrosis (CF), Pseudomonas aeruginosa causes persistent biofilm infection that is commonly treated with aminoglycoside antibiotics such as tobramycin. However, sublethal concentrations of this aminoglycoside were previously shown to increase biofilm formation by P. aeruginosa, but the underlying adaptive mechanisms still remain elusive. Herein, we combined confocal laser scanning microscope analyses, proteomics profiling, gene expression assays and phenotypic studies to unravel P. aeruginosa potential adaptive mechanisms in response to tobramycin exposure during biofilm growth. Under this condition, we show that the modified biofilm architecture is related at least in part to increased extracellular DNA (eDNA) release, most likely as a result of biofilm cell death. Furthermore, the activity of quorum sensing (QS) systems was increased, leading to higher production of QS signaling molecules. We also demonstrate upon tobramycin exposure an increase in expression of the PrrF small regulatory RNAs, as well as expression of iron uptake systems. Remarkably, biofilm biovolumes and eDNA relative abundances in pqs and prrF mutant strains decrease in the presence of tobramycin. Overall, our findings offer experimental evidences for a potential adaptive mechanism linking PrrF sRNAs, QS signaling, biofilm cell death, eDNA release, and tobramycin-enhanced biofilm formation in P. aeruginosa. These specific adaptive mechanisms should be considered to improve treatment strategies against P. aeruginosa biofilm establishment in CF patients' lungs.

PMID: 32439924 [PubMed - in process]

IVS8-5T Allele of CFTR is the Risk Factor in Chronic Pancreatitis, Especially in Idiopathic Chronic Pancreatitis.

Am J Med Sci. 2020 Apr 25;:

Authors: Jiang M, Li Z, Fu S, Xu Y, Tan Y, Jia W, Jiang Z, Mo N, Wei X, Zhang R, Zhang Z, Jiang G, Yang X

Abstract
BACKGROUND: Cystic fibrosis transmembrane conductance regulator IVS8-5T gene variation appears to be associated with a higher risk of chronic pancreatitis (CP); however, there is inconsistency between previous reported studies. Here, we performed a meta-analysis to investigate this relationship.
MATERIALS AND METHODS: PubMed and WANFANG databases were searched for the case-control studies that contained Patients with CP with IVS8-5T variation. Odd ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the relevance of IVS8-5T gene variation and CP.
RESULTS: Analysis showed that the frequency of the 5T allele was significantly higher in CP subjects than that in control subjects (OR = 1.43, 95% CI: 1.13-1.81, I2 = 1.2%). Based on the subgroup analysis stratified by etiology, the 5T allele was associated with a higher risk of idiopathic chronic pancreatitis (ICP) (OR = 1.80, 95% CI: 1.18-2.76, I2 = 0.0%) and not alcoholic CP (OR = 2.14, 95% CI: 0.98-4.66, I2 = 0.0%). Further study indicated that the 5T allele was related to higher ICP prevalence in the European population (OR = 1.79, 95% CI: 1.06-3.03, I2 = 0.0%). In contrast, there was no significant difference between ICP subjects and healthy controls within the Asian population (OR = 1.84, 95% CI: 0.91-3.72, I2 = 38.0%).
CONCLUSIONS: Cystic fibrosis transmembrane conductance regulator IVS8-5T is a risk factor in patients with CP. IVS8-5T variation may play a significant role in the occurrence of ICP, especially in the European population.

PMID: 32439152 [PubMed - as supplied by publisher]

Integrating latent classes in the Bayesian shared parameter joint model of longitudinal and survival outcomes.

Stat Methods Med Res. 2020 May 21;:962280220924680

Authors: Andrinopoulou ER, Nasserinejad K, Szczesniak R, Rizopoulos D

Abstract
Cystic fibrosis is a chronic lung disease requiring frequent lung-function monitoring to track acute respiratory events (pulmonary exacerbations). The association between lung-function trajectory and time-to-first exacerbation can be characterized using joint longitudinal-survival modeling. Joint models specified through the shared parameter framework quantify the strength of association between such outcomes but do not incorporate latent sub-populations reflective of heterogeneous disease progression. Conversely, latent class joint models explicitly postulate the existence of sub-populations but do not directly quantify the strength of association. Furthermore, choosing the optimal number of classes using established metrics like deviance information criterion is computationally intensive in complex models. To overcome these limitations, we integrate latent classes in the shared parameter joint model through a fully Bayesian approach. To choose the optimal number of classes, we construct a mixture model assuming more latent classes than present in the data, thereby asymptotically "emptying" superfluous latent classes, provided the Dirichlet prior on class proportions is sufficiently uninformative. Model properties are evaluated in simulation studies. Application to data from the US Cystic Fibrosis Registry supports the existence of three sub-populations corresponding to lung-function trajectories with high initial forced expiratory volume in 1 s (FEV1), rapid FEV1 decline, and low but steady FEV1 progression. The association between FEV1 and hazard of exacerbation was negative in each class, but magnitude varied.

PMID: 32438854 [PubMed - as supplied by publisher]

Pharmacophore-Based Design of New Chemical Scaffolds as Translational Readthrough-Inducing Drugs (TRIDs).

ACS Med Chem Lett. 2020 May 14;11(5):747-753

Authors: Tutone M, Pibiri I, Perriera R, Campofelice A, Culletta G, Melfi R, Pace A, Almerico AM, Lentini L

Abstract
Translational readthrough-inducing drugs (TRIDs) rescue the functional full-length protein expression in genetic diseases, such as cystic fibrosis, caused by premature termination codons (PTCs). Small molecules have been developed as TRIDs to trick the ribosomal machinery during recognition of the PTC. Herein we report a computational study to identify new TRID scaffolds. A pharmacophore approach was carried out on compounds that showed readthrough activity. The pharmacophore model applied to screen different libraries containing more than 87000 compounds identified four hit-compounds presenting scaffolds with diversity from the oxadiazole lead. These compounds have been synthesized and tested using the Fluc reporter harboring the UGA PTC. Moreover, the cytotoxic effect and the expression of the CFTR protein were evaluated. These compounds, a benzimidazole derivative (NV2899), a benzoxazole derivative (NV2913), a thiazole derivative (NV2909), and a benzene-1,3-disulfonate derivative (NV2907), were shown to be potential new lead compounds as TRIDs, boosting further efforts to address the optimization of the chemical scaffolds.

PMID: 32435380 [PubMed]

APPEAL-1: A pan-European survey of patient/caregiver perceptions of peanut allergy management.

Allergy. 2020 May 21;:

Authors: Blumchen K, DunnGalvin A, Timmermans F, Regent L, Schnadt S, Podestà M, Sánchez A, Couratier P, Feeney M, Hjorth B, Patel R, Lush T, Ryan R, Vereda A, Fisher HR, Fernández-Rivas M

Abstract
BACKGROUND: Peanut allergy (PA) is associated with marked quality-of-life (QoL) impairment. However, data are lacking on the experience and impact of living with PA from the perspectives of persons with PA (PwPA) and their caregivers. Allergy to Peanuts imPacting Emotions And Life study 1 (APPEAL-1) was a pan-European survey investigating these perspectives. This first of two articles reports clinical characteristics of PwPA and PA management practices.
METHODS: APPEAL-1 was a quantitative, online survey conducted in eight European countries, developed by eight representatives of patient advocacy groups and five healthcare professionals and researchers. Eligible participants included adults with PA and parents/caregivers of PwPA who responded by self-report and provided proxy-report for the PwPA under their care. Data were summarised using nonweighted descriptive statistics.
RESULTS: Of 1846 completed/analysed questionnaires, 528 were from adults with PA (self-report); 437 by proxy for children with PA (34 aged 0-3 years, 287 aged 4-12 years, 116 aged 13-17 years); 881 from parents/caregivers (self-report). Of PwPA (N=965), 95% reported diagnosis by healthcare professionals, mostly by clinical history and peanut-specific allergy testing. Rates of allergic rhinitis, asthma, and other food allergies in PwPA were 50%, 42%, and 79%, respectively. Only 31% of PwPA received HCP advice/support following their worst allergic reaction, and 28% had not been prescribed an adrenaline auto-injector. Results were similar by country but varied by age group.
CONCLUSIONS: The APPEAL-1 findings contribute to greater understanding of PA impact on PwPA, caregivers, and family members and the need for improved PA management across Europe.

PMID: 32438514 [PubMed - as supplied by publisher]

Assessing Human Airway Epithelial Progenitor Cells for Cystic Fibrosis Cell Therapy.

Am J Respir Cell Mol Biol. 2020 May 21;:

Authors: Lee RE, Miller SM, Mascenik TM, Lewis CA, Dang H, Boggs ZH, Tarran R, Randell SH

Abstract
Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane regulator (CFTR) gene. Pharmacologic therapies directed at CFTR have been developed but are not effective for mutations that result in little or no mRNA or protein expression. Cell therapy is a potential mutation-agnostic approach to treatment. One strategy is to harvest human bronchial epithelial cells (HBECs) for gene addition or genetic correction, followed by expansion and engraftment. This approach will require cells to grow extensively while retaining their ability to reconstitute CFTR activity. We hypothesized that conditionally reprogrammed cell (CRC) technology, namely growth in the presence of irradiated feeder cells and a Rho kinase inhibitor, would enable expansion while maintaining cell capacity to express functional CFTR. Our goal was to compare expression of the basal cell marker NGFR and 3D bronchosphere colony forming efficiency (CFE) in early and later passage HBECs grown using non-proprietary bronchial epithelial growth medium or the CRC method. Cell number and CFTR activity were determined in a competitive repopulation assay employing chimeric air-liquid interface (ALI) cultures. HBECs expanded using the CRC method expressed the highest NGFR levels, had the greatest 3D CFE at later passage, generated greater cell numbers in chimeric cultures, and most effectively reconstituted CFTR activity. In our study, the HBEC ALI model, an informative testing platform proven vital for the development of other CF therapies, illustrated that cells grown by CRC technology or equivalent methods may be useful for cell therapy of CF.

PMID: 32437238 [PubMed - as supplied by publisher]

Chronic cough in adults.

Eur J Intern Med. 2020 May 17;:

Authors: Spanevello A, Beghé B, Visca D, Fabbri LM, Papi A

Abstract
Cough, a defense mechanism for clearing the airways of secretions, exudate, or foreign bodies, may become a troublesome symptom. Chronic cough, one of the most frequent symptoms requiring medical attention, is often not due to identifiable causes in adults. Chronic productive cough defines chronic bronchitis, and thus is present in 100% of these patients, and frequently in patients with bronchiectasis, cystic fibrosis, and chronic infectious respiratory diseases. However, chronic cough is most frequently dry. Thus, chronic cough in adults is a difficult syndrome requiring multidisciplinary approaches, particularly to diagnose and treat the most frequent identifiable causes, but also to decide which patients may benefit by treating the central cough hypersensitivity by neuromodulatory therapy and/or non-pharmacologic treatment (speech pathology therapy). Recent guidelines provide algorithms for diagnosis and assessment of cough severity; particularly chronic cough in adults. After excluding life-threatening diseases, chronic cough due to identifiable causes (triggers and/or diseases), particularly smoking and/or the most frequent diseases (asthma, chronic bronchitis, chronic obstructive pulmonary disease, eosinophilic bronchitis, and adverse reactions to drugs [angiotensin-converting enzyme inhibitors and sitagliptin]) should be treated by avoiding triggers and/or according to guidelines for each underlying disease. In patients with troublesome chronic cough due to unknown causes or persisting even after adequate avoidance of triggers, and/or treatment of the underlying disease(s), a symptomatic approach with neuromodulators and/or speech pathology therapy should be considered. Additional novel promising neuromodulatory agents in clinical development (e.g., P2X3 inhibitors) will hopefully become available in the near future.

PMID: 32434660 [PubMed - as supplied by publisher]

Correction to: Assessment of stigma in patients with cystic fibrosis.

BMC Pulm Med. 2020 May 20;20(1):145

Authors: Pakhale S, Armstrong M, Holly C, Edjoc R, Gaudet E, Aaron S, Tasca G, Cameron W, Balfour L

Abstract
An amendment to this paper has been published and can be accessed via the original article.

PMID: 32434540 [PubMed - in process]

Treatment of human T-cell acute lymphoblastic leukemia cells with CFTR inhibitor CFTRinh-172.

Leuk Res. 2019 11;86:106225

Authors: Liu M, Liao H, Chen Y, Lin Z, Liu Y, Zhang X, Chan HC, Sun H

Abstract
Our previous studies have demonstrated that a previously unrecognized role of CFTR in hematopoiesis and acute leukemia. Here, we show that CFTR inhibitor CFTR-inh172 possesses ability to inhibit human T-cell acute lymphoblastic leukemia cells. In detail, CFTR-inh172 inhibited cell proliferation, promoted apoptosis and arrested the cell cycle in human T-cell acute lymphoblastic leukemia cell CCRF-CEM, JURKAT and MOLT-4. Furthermore, transcriptome analysis reveals that CFTR-inh172 induces significant alteration of gene expression related to apoptosis and proliferation. These findings demonstrate the potential of CFTR inhibitor CFTR-inh172 in human T-cell acute lymphoblastic leukemia treatment.

PMID: 31541940 [PubMed - indexed for MEDLINE]

How FtsEX localizes to the Z ring and interacts with FtsA to regulate cell division.

Mol Microbiol. 2019 09;112(3):881-895

Authors: Du S, Henke W, Pichoff S, Lutkenhaus J

Abstract
In Escherichia coli, FtsEX, a member of the ABC transporter superfamily, is involved in regulating the assembly and activation of the divisome to couple cell wall synthesis to cell wall hydrolysis at the septum. Genetic studies indicate FtsEX acts on FtsA to begin the recruitment of the downstream division proteins but blocks septal PG synthesis until a signal is received that divisome assembly is complete. However, the details of how FtsEX localizes to the Z ring and how it interacts with FtsA are not clear. Our results show that recruitment of FtsE and FtsX is codependent and suggest that the FtsEX complex is recruited through FtsE interacting with the conserved tail of FtsZ (CCTP), thus adding FtsEX to a growing list of proteins that interacts with the CCTP of FtsZ. Furthermore, we find that the N-terminus of FtsX is not required for FtsEX localization to the Z ring but is required for its functions in cell division indicating that it interacts with FtsA. Taken together, these results suggest that FtsEX first interacts with FtsZ to localize to the Z ring and then interacts with FtsA to promote divisome assembly and regulate septal PG synthesis.

PMID: 31175681 [PubMed - indexed for MEDLINE]

Ceftolozane/Tazobactam for Treating Children With Exacerbations of Cystic Fibrosis Due to Pseudomonas aeruginosa: A Review of Available Data.

Front Pediatr. 2020;8:173

Authors: Garazzino S, Altieri E, Silvestro E, Pruccoli G, Scolfaro C, Bignamini E

Abstract
Ceftolozane-tazobactam is a novel fifth-generation cephalosporin/β-lactamase inhibitor combination recently approved for treatment of both complicated intra-abdominal and urinary tract infections in adults. Considering its potent bactericidal activity against Pseudomonas aeruginosa, it might represent an important option also for treating children with exacerbations of cystic fibrosis due to Pseudomonas aeruginosa when other alternative treatments have been exhausted. We hereby review available data on the use of ceftolozane-tazobactam in children, focusing on cystic fibrosis.

PMID: 32432060 [PubMed]

NtrBC Regulates Invasiveness and Virulence of Pseudomonas aeruginosa During High-Density Infection.

Front Microbiol. 2020;11:773

Authors: Alford MA, Baghela A, Yeung ATY, Pletzer D, Hancock REW

Abstract
Pseudomonas aeruginosa is an opportunistic pathogen that is a major cause of nosocomial and chronic infections contributing to morbidity and mortality in cystic fibrosis patients. One of the reasons for its success as a pathogen is its ability to adapt to a broad range of circumstances. Here, we show the involvement of the general nitrogen regulator NtrBC, which is structurally conserved but functionally diverse across species, in pathogenic and adaptive states of P. aeruginosa. The role of NtrB and NtrC was examined in progressive or chronic infections, which revealed that mutants (ΔntrB, ΔntrC, and ΔntrBC) were reduced in their ability to invade and cause damage in a high-density abscess model in vivo. Progressive infections were established with mutants in the highly virulent PA14 genetic background, whereas chronic infections were established with mutants in the less virulent clinical isolate LESB58 genetic background. Characterization of adaptive lifestyles in vitro confirmed that the double ΔntrBC mutant demonstrated >40% inhibition of biofilm formation, a nearly complete inhibition of swarming motility, and a modest decrease and altered surfing motility colony appearance; with the exception of swarming, single mutants generally had more subtle or no changes. Transcriptional profiles of deletion mutants under swarming conditions were defined using RNA-Seq and unveiled dysregulated expression of hundreds of genes implicated in virulence in PA14 and LESB58 chronic lung infections, as well as carbon and nitrogen metabolism. Thus, transcriptional profiles were validated by testing responsiveness of mutants to several key intermediates of central metabolic pathways. These results indicate that NtrBC is a global regulatory system involved in both pathological and physiological processes relevant to the success of Pseudomonas in high-density infection.

PMID: 32431676 [PubMed]

Functional rescue of an ABCB11 mutant by ivacaftor: a new targeted pharmacotherapy approach in bile salt export pump deficiency.

Liver Int. 2020 May 20;:

Authors: Mareux E, Lapalus M, Amzal R, Almes M, Aït-Slimane T, Delaunay JL, Adnot P, Collado-Hilly M, Davit-Spraul A, Falguières T, Callebaut I, Gonzales E, Jacquemin E

Abstract
BACKGROUND & AIM: The canalicular bile salt export pump (BSEP/ABCB11) of hepatocytes is the main adenosine triphosphate (ATP)-binding cassette (ABC) transporter responsible for bile acid secretion. Mutations in ABCB11 cause several cholestatic diseases, including progressive familial intrahepatic cholestasis type 2 (PFIC2) often lethal in absence of liver transplantation. We investigated in vitro the effect and potential rescue of a BSEP mutation by ivacaftor, a clinically approved cystic fibrosis transmembrane conductance regulator (CFTR/ABCC7) potentiator.
METHODS: The p.T463I mutation, identified in a PFIC2 patient and located in a highly conserved ABC transporter motif, was studied by 3D structure modeling. The mutation was reproduced in a plasmid encoding a rat Bsep-green fluorescent protein. After transfection, mutant expression was studied in Can 10 cells. Taurocholate transport activity and ivacaftor effect were studied in Madin-Darby canine kidney (MDCK) clones co-expressing the rat sodium-taurocholate co-transporting polypeptide (Ntcp/Slc10A1).
RESULTS: As the wild-type protein, BsepT463I was normally targeted to the canalicular membrane of Can 10 cells. As predicted by 3D structure modeling, taurocholate transport activity was dramatically low in MDCK clones expressing BsepT463I . Ivacaftor treatment increased by 1.7-fold taurocholate transport activity of BsepT463I (p<0.0001), reaching 95% of Bsepwt activity. These data suggest that the p.T463I mutation impairs ATP-binding, resulting in Bsep dysfunction that can be rescued by ivacaftor.
CONCLUSION: These results provide experimental evidence of ivacaftor therapeutic potential for selected patients with PFIC2 caused by ABCB11 missense mutations affecting BSEP function. This could represent a significant step forward for the care of patients with BSEP deficiency.

PMID: 32433800 [PubMed - as supplied by publisher]

ERp29 as a regulator of Insulin biosynthesis.

PLoS One. 2020;15(5):e0233502

Authors: Viviano J, Brecker M, Ferrara-Cook C, Suaud L, Rubenstein RC

Abstract
The environment within the Endoplasmic Reticulum (ER) influences Insulin biogenesis. In particular, ER stress may contribute to the development of Type 2 Diabetes (T2D) and Cystic Fibrosis Related Diabetes (CFRD), where evidence of impaired Insulin processing, including elevated secreted Proinsulin/Insulin ratios, are observed. Our group has established the role of a novel ER chaperone ERp29 (ER protein of 29 kDa) in the biogenesis of the Epithelial Sodium Channel, ENaC. The biogenesis of Insulin and ENaC share may key features, including their potential association with COP II machinery, their cleavage into a more active form in the Golgi or later compartments, and their ability to bypass such cleavage and remain in a less active form. Given these similarities we hypothesized that ERp29 is a critical factor in promoting the efficient conversion of Proinsulin to Insulin. Here, we confirmed that Proinsulin associates with the COP II vesicle cargo recognition component, Sec24D. When Sec24D expression was decreased, we observed a corresponding decrease in whole cell Proinsulin levels. In addition, we found that Sec24D associates with ERp29 in co-precipitation experiments and that ERp29 associates with Proinsulin in co-precipitation experiments. When ERp29 was overexpressed, a corresponding increase in whole cell Proinsulin levels was observed, while depletion of ERp29 decreased whole cell Proinsulin levels. Together, these data suggest a potential role for ERp29 in regulating Insulin biosynthesis, perhaps in promoting the exit of Proinsulin from the ER via Sec24D/COPII vesicles.

PMID: 32433667 [PubMed - as supplied by publisher]

TNFα and IL-17 Alkalinize Airway Surface Liquid through CFTR and Pendrin.

Am J Physiol Cell Physiol. 2020 May 20;:

Authors: Rehman T, Thornell IM, Pezzulo AA, Thurman AL, Romano Ibarra GS, Karp PH, Tan P, Duffey ME, Welsh MJ

Abstract
The pH of airway surface liquid (ASL) is a key factor that determines respiratory host defense; ASL acidification impairs and alkalinization enhances key defense mechanisms. Under healthy conditions, airway epithelia secrete base (HCO3¯) and acid (H+) to control ASL pH (pHASL). Neutrophil-predominant inflammation is a hallmark of several airway diseases, and TNFα and IL-17 are key drivers. However, how these cytokines perturb pHASL regulation is uncertain. In primary cultures of differentiated human airway epithelia, TNFα decreased and IL-17 did not change pHASL. However, the combination (TNFα+IL-17) markedly increased pHASL by increasing HCO3¯ secretion. TNFα+IL-17 increased expression and function of two apical HCO3¯ transporters, CFTR anion channels and pendrin Cl-/HCO3- exchangers. Both were required for maximal alkalinization. TNFα+IL-17 induced pendrin expression primarily in secretory cells where it was co-expressed with CFTR. Interestingly, significant pendrin expression was not detected in CFTR-rich ionocytes. These results indicate that TNFα+IL-17 stimulate HCO3- secretion via CFTR and pendrin to alkalinize ASL, which may represent an important defense mechanism in inflamed airways.

PMID: 32432926 [PubMed - as supplied by publisher]

The FOXA1 transcriptional network coordinates key functions of primary human airway epithelial cells.

Am J Physiol Lung Cell Mol Physiol. 2020 May 20;:

Authors: Paranjapye A, Mutolo MJ, Ebron JS, Leir SH, Harris A

Abstract
The differentiated functions of the human airway epithelium are coordinated by a complex network of transcription factors. These include the pioneer factors Forkhead box A1 and A2 (FOXA1 and FOXA2), which are well studied in several tissues, but their role in airway epithelial cells is poorly characterized. Here we define the cistrome of FOXA1 and FOXA2 in primary human bronchial epithelial (HBE) cells by ChIP-seq. Next, siRNA- mediated depletion of each factor is used to investigate their transcriptome by RNA-seq. We found that, as predicted from their DNA-binding motifs, genome-wide occupancy of the two factors showed substantial overlap, however their global impact on gene expression differed. FOXA1 is an abundant transcript in HBE cells, while FOXA2 is expressed at low levels and both these factors likely exhibit auto-regulation and cross-regulation. FOXA1 regulated loci are involved in cell adhesion and the maintenance of epithelial cell identity, particularly through repression of genes associated with epithelial to mesenchymal transition (EMT). FOXA1 also directly targets other transcription factors with a known role in the airway epithelium such as SAM-pointed domain-containing Ets-like factor (SPDEF). The intersection of the cistrome and transcriptome for FOXA1 revealed enrichment of genes involved in epithelial development and tissue morphogenesis. Moreover, depletion of FOXA1 was shown to reduce the transepithelial resistance of HBE cells confirming the role of this factor in maintaining epithelial barrier integrity.

PMID: 32432922 [PubMed - as supplied by publisher]

How do cystic fibrosis patients experience parenthood? A systematic review.

J Health Psychol. 2020 May 20;:1359105320916539

Authors: Jacob A, Journiac J, Fischer L, Astrologo L, Flahault C

Abstract
Improved treatments for cystic fibrosis allow more patients to become parents. This article presents a systematic review of literature on cystic fibrosis patients' experience of parenthood. Five databases (Cairn, Cochrane Library, PsycINFO, PubMed and ScienceDirect) produced 2335 documents that were screened. In total, 13 documents were retained and assessed with validated criteria. Five themes related to cystic fibrosis parenthood were discovered: population presentation, health and treatment adherence, adjustments, role of professionals and pressured temporality. Parenthood requires an important reorganisation of daily life in order to remain capable of childcare. Regardless of negative health impacts, cystic fibrosis parents have a positive outlook on parenthood.

PMID: 32431218 [PubMed - as supplied by publisher]

The liaison between respiratory failure and high blood pressure: evidence from COVID-19 patients.

Eur Respir J. 2020 May 19;:

Authors: Vicenzi M, Di Cosola R, Ruscica M, Ratti A, Rota I, Rota F, Bollati V, Aliberti S, Blasi F

PMID: 32430432 [PubMed - as supplied by publisher]

Multivariate joint modeling to identify markers of growth and lung function decline that predict cystic fibrosis pulmonary exacerbation onset.

BMC Pulm Med. 2020 May 19;20(1):142

Authors: Andrinopoulou ER, Clancy JP, Szczesniak RD

Abstract
BACKGROUND: Attenuated decreases in lung function can signal the onset of acute respiratory events known as pulmonary exacerbations (PEs) in children and adolescents with cystic fibrosis (CF). Univariate joint modeling facilitates dynamic risk prediction of PE onset and accounts for measurement error of the lung function marker. However, CF is a multi-system disease and the extent to which simultaneously modeling growth and nutrition markers improves PE predictive accuracy is unknown. Furthermore, it is unclear which routinely collected clinical indicators of growth and nutrition in early life predict PE onset in CF.
METHODS: Using a longitudinal cohort of 17,100 patients aged 6-20 years (US Cystic Fibrosis Foundation Patient Registry; 2003-2015), we fit a univariate joint model of lung-function decline and PE onset and contrasted its predictive performance with a class of multivariate joint models that included combinations of growth markers as additional submodels. Outcomes were longitudinal lung function (forced expiratory volume in 1 s of % predicted), percentiles of body mass index, weight-for-age and height-for-age and PE onset. Relevant demographic/clinical covariates were included in submodels. We implemented a univariate joint model of lung function and time-to-PE and four multivariate joint models including growth outcomes.
RESULTS: All five joint models showed that declining lung function corresponded to slightly increased risk of PE onset (hazard ratio from univariate joint model: 0.97, P < 0.0001), and all had reasonable predictive accuracy (cross-validated area under the receiver-operator characteristic curve > 0.70). None of the growth markers alongside lung function as outcomes in multivariate joint modeling appeared to have an association with hazard of PE. Jointly modeling only lung function and PE onset yielded the most accurate (area under the receiver-operator characteristic curve = 0.75) and precise (narrowest interquartile range) predictions. Dynamic predictions were accurate across forecast horizons (0.5, 1 and 2 years) and precision improved with age.
CONCLUSIONS: Including growth markers via multivariate joint models did not yield gains in prediction performance, compared to a univariate joint model with lung function. Individualized dynamic predictions from joint modeling could enhance physician monitoring of CF disease progression by providing PE risk assessment over a patient's clinical course.

PMID: 32429862 [PubMed - in process]

Analysis of CFTR Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients.

Genes (Basel). 2020 May 15;11(5):

Authors: Petrova NV, Kashirskaya NY, Vasilyeva TA, Kondratyeva EI, Zhekaite EK, Voronkova AY, Sherman VD, Galkina VA, Ginter EK, Kutsev SI, Marakhonov AV, Zinchenko RA

Abstract
The distribution and frequency of the CFTR gene mutations vary considerably between countries and ethnic groups. Russians are an East Slavic ethnic groups are native to Eastern Europe. Russians, the most numerous people of the Russian Federation (RF), make about 80% of the population. The aim is to reveal the molecular causes of CF in ethnic Russian patients as comprehensively as possible. The analysis of most common CFTR mutations utilized for CF diagnosis in multiethnic RF population accounts for about 83% of all CF-causing mutations in 1384 ethnic Russian patients. Variants c.1521_1523delCTT (F508del), c.54-5940_273+10250del21kb (CFTRdele2,3), c.2012delT (2143delT), c.2052_2053insA (2184insA), and c.3691delT (3821delT) are most typical for CF patients of Russian origin. DNA of 154 CF patients, Russian by origin, in whom at least one mutant allele was not previously identified (164 CF alleles), was analyzed by Sanger sequencing followed by the multiplex ligase-dependent probe amplification (MLPA) method. In addition to the 29 variants identified during the previous test for common mutations, 91 pathogenic CFTR variants were also revealed: 29 missense, 19 nonsense, 14 frame shift in/del, 17 splicing, 1 in frame ins, and 11 copy number variations (CNV). Each of the 61 variants was revealed once, and 17 twice. Each of the variants c.1209G>C (E403D), c.2128A>T (K710X), c.3883delA (4015delA), and c.3884_3885insT (4016insT) were detected for three, c.1766+1G>A (1898+1G>A) and c.2834C>T (S945L) for four, c.1766+1G>C (1898+1G>C) and c.(743+1_744-1)_(1584+1_1585-1)dup (CFTRdup6b-10) for five, c.2353C>T (R785X) and c.4004T>C (L1335P) for six, c.3929G>A (W1310X) for seven, c.580-1G>T (712-1G>T for eight, and c.1240_1244delCAAAA (1365del5) for 11 unrelated patients. A comprehensive analysis of CFTR mutant alleles with sequencing followed by MLPA, allowed not only the identification of 163 of 164 unknown alleles in our patient sample, but also expansion of the mutation spectrum with novel and additional frequent variants for ethnic Russians.

PMID: 32429104 [PubMed - in process]